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A systematic review and meta-analysis of studiesevaluating the performance of point-of-care tests for

human papillomavirus screeningHelen Kelly, Philippe Mayaud, Michel Segondy, Nitika Pant Pai, Rosanna

Peeling

To cite this version:Helen Kelly, Philippe Mayaud, Michel Segondy, Nitika Pant Pai, Rosanna Peeling. A systematicreview and meta-analysis of studies evaluating the performance of point-of-care tests for human papil-lomavirus screening. Sexually Transmitted Infections, BMJ Publishing Group, 2017, 93 (S4), pp.S36-S45. �10.1136/sextrans-2016-053070�. �hal-01738296�

S36 Kelly H, et al. Sex Transm Infect 2017;93:S36–S45. doi:10.1136/sextrans-2016-053070

Review

A systematic review and meta-analysis of studies evaluating the performance of point-of-care tests for human papillomavirus screeningHelen Kelly,1 Philippe Mayaud,1 Michel Segondy,2 Nitika Pant Pai,3 Rosanna W Peeling1

SummaryBackground High-risk human papillomavirus (HPV) is a necessary cause of high-grade cervical intraepithelial neoplasia (grade 2 or higher, CIN2+). Simplified and rapid HPV DNA assays designed for use in resource-limited settings have recently become available.methods We performed a systematic review and meta-analysis by searching Medline, Embase, Global Health and CINAHL databases for studies from 1 January 2004 to 25 February 2017 that reported the performance of careHPV or OncoE6 for the detection of histological CIN2+ in cervical cancer screening. We used bivariate models to estimate pooled sensitivity and specificity for CIN2+ and CIN3+.results A total of 29 657 women were included from seven studies evaluating the performance of careHPV for the detection of CIN2+ and four studies among 27 845 women for the detection of CIN3+. The pooled prevalence for CIN2+ and CIN3+ was 2.3% and 1.1%, respectively. careHPV had sensitivity and specificity of 88.1% (95% CI 81.4 to 92.7) and 83.7% (95% CI 74.9 to 89.8), respectively, for CIN2+ and 90.3% (95% CI 83.4 to 94.5) and 85.3% (95% CI 73.1 to 92.5), respectively, for CIN3+, using clinician-collected cervical specimen. The corresponding pooled estimates using self-collected vaginal swabs were 73.6% (95% CI 64.9 to 80.8) and 88.0% (95% CI 79.1 to 93.5) for CIN2+ and 75.2% (95% CI 66.8 to 82.0) and 90.6% (95% CI 83.4 to 94.9) for CIN3+. Two studies using OncoE6 reported sensitivity and specificity ranging from 31.3% to 42.4% and 99.1%–99.4% for CIN2+, and 53.5% and 98.9% for CIN3+ for one study.Conclusion CareHPV has good sensitivity and specificity for the detection of CIN2+ and CIN3+, but sensitivity was lower using self-collected vaginal samples. The specificity is lower in high HPV prevalence populations such as women living with HIV. OncoE6 assay warrants further evaluation.

IntroduCtIonHuman papillomavirus (HPV) is a necessary cause of invasive cervical cancer (ICC),1 2 which affects nearly 500 000 women around the world every year with a mortality of more than 270 000, 80% of whom live in low and middle income (LMIC) countries.3 Cytology-based programmes have been the main approach for screening, but these are not often available in most of the low/middle-income countries.4

The WHO 2014 cervical cancer screening guidelines recommend that screening should be performed at least once between the ages of 39 and 49 years, and this may be extended to women younger than 30 years if there is evidence of high risk for high-grade cervical intraepithelial neoplasia (grade 2 and above, CIN2+).5 6 However, cervical cancer screening coverage, and linkage to care, is low in LMIC countries where infrastructure and personnel requirements put high demands on the health systems.4 Cytology-based programmes have improved cervical cancer control in developed countries, but implementation in LMIC countries is constrained by cost, lack of infrastructure and trained staff, and lag time between sample collec-tion and availability of test result, leading to delays or losses in management.7 Visual inspection of the cervix using acetic acid (VIA) or Lugol’s iodine (VILI) is frequently practised in low-resource settings as it can be performed by trained midwives and nurses, and requires simple tools to perform (speculum, acetic acid, Lugol’s iodine, lamp). However, frequent training and supervision is required, and the wide variation in its performance is attributed to the subjective nature of test interpre-tation.7–9 An important advantage of visual inspec-tion is the possibility to link screening to immediate management.

Randomised controlled trials have shown that HPV-DNA-based screening allows for earlier diag-nosis of high-grade CIN and can be more effec-tive in prevention of ICC.10 A single round of the Digene Hybrid Capture 2 (HC2) test that detects 13 high-risk (HR) HPV types (a qualitative assay that does not distinguish the individual genotypes) has shown to halve the rate of ICC (HR=0.47, 95% CI 0.32 to 0.69) and ICC-related mortality (HR=0.52, 95% CI 0.33 to 0.83) compared with standard-of-care among 131 746 women aged 30–59 years in India.10 However, the assay is expensive and requires good logistical platforms. The addition of good-performance, rapid and affordable point-of-care (POC) tests would considerably enhance access to HPV testing in LMIC. The careHPV test (Qiagen) is based on a simplification of the HC2 test platform. It detects 14 HR-HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) and is optimised for low/middle-income countries: the assay needs only a small bench-top work space (about 25×50 cm), no mains electricity (battery operated) or running water, and can be done by

to cite: Kelly H, Mayaud P, Segondy M, et al. Sex Transm Infect 2017;93:S36–S45.

► Additional material is published online only. To view please visit the journal online (http:// dx. doi. org/ 10. 1136/ sextrans- 2016- 053070).

1London School of Hygiene and Tropical Medicine, London, UK2INSERM U1058 and University Hospital (CHRU), Montpellier, France3Department of Epidemiology, McGill University, Montreal, Canada

Correspondence toDr Helen Kelly, Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E7HT, UK; helen. kelly@ lshtm. ac. uk

Received 7 March 2017Revised 3 July 2017Accepted 9 July 2017

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S37Kelly H, et al. Sex Transm Infect 2017;93:S36–S45. doi:10.1136/sextrans-2016-053070

review

trained staff in roughly 2.5 hours and has a longer shelf-life compared with the HC2 assay. New molecular tests with similar characteristics, although with different targets, are becoming also available on the market. The OncoE6 test (Arbor Vita) is a lateral flow immunoassay that detects the E6 oncoprotein from HPV16, HPV18 and HPV45, which cause approximately 75% of ICC.11

The purpose of this review was to identify tests for the detec-tion of HR-HPV that met the ASSURED criteria,12 conduct a systematic review of the literature and summarise their perfor-mance characteristics for the detection of CIN2+.

methodSIndex testsOnly rapid/POC tests for the detection of HR HPV that met the ASSURED criteria were included (Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment-free and Deliverable to end-users).12 HR-HPV types were defined using the current International Agency for Research on Cancer classification13: ‘carcinogenic to humans’ (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) and ‘probable carcinogenic’ (HPV68).

reference or gold standard testStudies were included if HPV-DNA tests were assessed against a histological endpoint of CIN grade 2 or higher (CIN2+). Studies with cytological endpoint assessment only were excluded

because of the lower sensitivity for cytology measures in detec-tion of high-grade disease.8

SearchWe searched Medline, Embase, Global Health and CINAHL databases for publications in the English language from 1 January 2004 to 31 December 2013 using search terms for human papillomavirus (HPV), cervical intraepithelial lesions (CIN), squamous intraepithelial lesions (SIL), HPV screening; Diagnostics; Point of Care; Rapid; Near patient; method; test; evaluation; performance and comparison. Reference lists of review articles and all articles identified in the systematic search were checked. An updated search was performed on 25 February 2017. All abstracts were screened by one author (HK).

Inclusion and exclusion criteriaEligibility criteria were defined using the PICOS (Population, Interventions, Comparisons, Outcomes, Study Design) criteria as shown in box 1. Studies evaluating the accuracy of any HPV-POC tests commercially available at the time of the review were considered for inclusion.

Studies were excluded if the index test was not a rapid test for HPV (ie, did not meet the ASSURED criteria), if diagnostic accuracies were not compared with a histological endpoint and if the studies did not report data to allow for calculation of diag-nostic accuracy.

Box 1 Inclusion criteria (PICoS)

PopulationAny sexually active populations consistent with the WHO screening guidelines in any geographical location, female only, include HIV-positive patients.

Interventions (index tests)Any commercially available technology used for HPV-POC testing in the field.

ComparatorsOther commercially available technology used for HPV testing.

reference standardInclude studies using an acceptable reference standard that satisfy the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist (Quality assessment—see online supplementary table 1). Acceptable reference standard—histology.

Sample typeVaginal or cervical swab.

outcomesEvaluations of accuracy. Include studies calculating sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV; including 95% CIs).

Study designCross-sectional or cohort studies evaluating HPV-POC tests against histological endpoint of CIN2+ or CIN3+.

otherEnglish language only, human subjects only, 1 January 2004 to 25 February 2017.

Figure 1 Flowchart for study selection.

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S38 Kelly H, et al. Sex Transm Infect 2017;93:S36–S45. doi:10.1136/sextrans-2016-053070

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data extractionFrom the consensus list, sensitivity and specificity measures were extracted by one author (HK) using a standardised form. For all studies, the following variables were recorded: year of study, study location, study population, outcomes of interest (histo-logical confirmed lesion CIN2+/CIN3+), HR-HPV prevalence and sensitivity and specificity for the detection of CIN2+ and CIN3+, where given.

methodological assessmentIncluded studies were assessed according to the QUADAS-2 checklist for reporting diagnostic accuracy14 (online supplemen-tary table 1).

Statistical analysisThe numbers of true positives, false positives, true negatives and false negatives were extracted where available. Where sensitivity and specificity measures only were given, data were extracted to calculate the numbers of true positives, false negatives, true negatives and false positives. Forest plots were generated to display sensitivity and specificity estimates.

meta-analysisThe bivariate model15 was used to estimate pooled sensitivity and specificity estimates using metandi and midas in STATA, whereby pairs of sensitivity and specificity are jointly analysed, incorporating any correlation that might exist between these two measures using a random-effects approach. Heterogeneity across studies was assessed using the I2 statistic.16

Separate meta-analyses were performed for the detection of CIN2+ and CIN3+ outcomes, and were also performed sepa-rately for studies that used different specimen types (cervical vs vaginal swabs).

To account for correlation between sensitivity and specificity, we used the hierarchical summary receiver operating char-acteristic (HSROC),17 which allows for threshold effects and between-study and within-study variability, by allowing both test accuracy to vary across studies. The heterogeneity in the forest plots were assessed by visually examining the confidence inter-vals (CIs) of individual studies, and in summary HSROC plots by examining the width of the prediction region, with a wider prediction region suggesting more heterogeneity.

Sensitivity analysisSensitivity analyses could not be performed due to lack of addi-tional covariate data. Formal assessment of publication bias was not performed due to low number of studies.

Data were analysed using Stata V.14 (Stata Statistical Software).This review was reported according to the Preferred Reporting

Items for Systematic Reviews and Meta-Analyses (PRISMA)18 and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines.19

reSultSSearch resultThe first review up to 31 December 2013 identified 1364 publi-cations through Medline, Embase, Global Health and CINAHL library searches, which reported performance measures for HPV DNA point-of-care tests for the detection of CIN2+ (figure 1), of which 1359 were excluded after abstract review because the assays did not meet the ASSURED criteria, leaving five publications for full-text review. Finally, two publications20 21 satisfied the inclusion criteria. An updated search performed until

25 February 2017 identified an additional four publications22–25 that satisfied the inclusion criteria. Two further publications26 27 were subsequently identified in June 2017. The reviews identi-fied only two tests that appeared to satisfy the ASSURED criteria (careHPV (Qiagen) targeting the HR-HPV types HPV16/18/31/33/35/39/45/51/52/56/58/59/66/68 and OncoE6 (Arbor Vita) targeting the HR-HPV types HPV16/18/45), which had publi-cation material that could be assessed. The characteristics of the included publications are summarised in Table 1. One publica-tion24 provided performance estimates for two countries and was considered as two separate populations in the analysis; one publication23 provided performance estimates for four countries and was considered as four separate populations in the analysis, and one publication27 provided performance estimates sepa-rately for women living with HIV (WLHIV) and HIV-negative women and was considered as two populations. This resulted in 12 separate populations included in the final analysis, among 29 657 women. Two studies measured the performance of careHPV for CIN2+ detection among 1215 WLHIV in Burkina Faso and South Africa,24 and Uganda.27

Among seven studies (twelve populations) evaluating the careHPV test (table 1), all evaluated the performance of careHPV test for the detection of CIN2+ and four studies (eight populations) evaluated its performance for the detec-tion of CIN3+20 22–24 using clinician-collected cervical swabs. Four studies (eight populations) evaluated the performance of careHPV for the detection of CIN2+20 22 23 27 and three studies (six populations) for CIN3+20 22 23 using self-sampled vaginal swabs. All studies evaluating the performance of careHPV used a cut-off of 1 pg/mL for defining test positivity.

Two studies evaluated the performance of OncoE6 test for the detection of CIN2+22 25 and one study for CIN3+22 using clini-cian-collected cervical swabs.

The CarehPV test for the detection of CIn2+ and CIn3+The sensitivity and specificity estimates for CIN2+ for indi-vidual populations are summarised in figure 2 (clinician-col-lected cervical swabs) and figure 3 (self-collected vaginal swabs). Sensitivity and specificity for CIN3+ for individual populations are summarised in figure 4 (clinician-collected cervical swab) and figure 5 (self-collected vaginal swab). The pooled summary estimates are summarised in table 2.

The careHPV test had a sensitivity of 88.1% (95% CI 81.4 to 92.7) and specificity of 83.7% (95% CI 74.9 to 89.8) for CIN2+ detection using clinician-collected cervical swabs (table 2), and a sensitivity of 73.6% (95% CI 64.9 to 80.8) and specificity of 88.0% (95% CI 79.1 to 93.5) using self-collected vaginal swabs.

The corresponding pooled estimates for sensitivity and speci-ficity for CIN3+ were 90.3% (95% CI 83.4 to 94.5) and 85.3% (95% CI 73.1 to 92.5), respectively, using cervical swabs and 75.2% (95% CI 66.8 to 82.0) and 90.6% (95% CI 83.4 to 94.9) using vaginal swabs. Heterogeneity across studies was high for both CIN2+ and CIN3+ outcomes (table 2).

When restricting the analysis to six studies (nine populations) among the general population of women using clinician-col-lected cervical swabs, the sensitivity for CIN2+ was similar to the overall pooled result (84.9%, 95% CI 76.8 to 90.5; table 2), but specificity was higher (88.6%, 95% CI 76.8 to 90.5). The pooled estimates for the 1215 WLHIV in Burkina Faso, South Africa and Uganda were 93.7% (95% CI 86.8 to 97.7) and 58.8% (95% CI 55.9 to 61.7) for sensitivity and specificity, respectively (data not shown).24 27

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S39Kelly H, et al. Sex Transm Infect 2017;93:S36–S45. doi:10.1136/sextrans-2016-053070

review

tabl

e 1

Char

acte

ristic

s of

incl

uded

stu

dies

aut

hor

loca

tion

Stud

y po

pula

tion

no

Spec

imen

typ

eSa

mpl

e si

zeSt

udy

popu

lati

onm

edia

n ag

e (IQ

r) o

r ag

e ra

nge

Prev

alen

ce

Biop

sy in

dica

tion

hr 

hPV

*CI

n2+

CIn

3+

Care

HPV

stud

ies

Sego

ndy 

et a

l24O

uaga

doug

ou,

Burk

ina

Faso

1Cl

inic

ian/

nurs

e-co

llect

ed

cerv

ical

sw

ab44

4W

LHIV

att

endi

ng H

IV tr

eatm

ent c

entr

es p

revi

ousl

y sc

reen

ed

for C

IN2+

36 (3

1–41

)46

.5%

2.0%

0.2%

Scre

en p

ositi

ve fo

r any

of:

VIA/

VILI

, cyt

olog

y >

ASCU

S, c

olpo

scop

y ab

norm

al

Joha

nnes

burg

, Sou

th

Afric

a2

Clin

icia

n/nu

rse-

colle

cted

ce

rvic

al s

wab

499

34 (3

0–40

)43

.8%

10.2

%2.

8%

Tuer

xun 

et a

l26Ch

ina—

Xinj

iang

3Cl

inic

ian/

nurs

e-co

llect

ed

cerv

ical

sw

ab21

2W

omen

scr

eeni

ng p

ositi

ve fo

r eith

er V

IA/V

ILI o

r cer

vica

l cy

tolo

gy (A

SCU

S+) a

t the

out

patie

nt d

epar

tmen

t of t

he

Affil

iate

d Tu

mor

Hos

pita

l of X

injia

ng M

edic

al U

nive

rsity

NR

35.4

%28

.3%

18.4

%Co

lpos

copy

was

per

form

ed to

det

erm

ine

posi

tive

resu

lts fr

om V

IA/V

ILI o

r cy

tolo

gy (A

SCU

S+),

and

dire

ct b

iops

y or

four

-qua

dran

t bio

psie

s w

ere

take

n.

Hist

olog

y re

ad b

y tw

o hi

stop

atho

logi

sts

Bans

il et

 al27

Uga

nda—

Kam

pala

an

d W

akis

o Di

stric

t4

Clin

icia

n-co

llect

ed c

ervi

cal +

se

lf-co

llect

ed v

agin

al s

wab

272

946

WLH

IV in

vite

d fo

r cer

vica

l can

cer s

cree

ning

HIV-

nega

tive

wom

en in

vite

d fo

r cer

vica

l can

cer s

cree

ning

NR

NR

44.9

%20

.2%

12.9

%1.

7%N

RN

RW

omen

who

scr

eene

d ne

gativ

e ad

vise

d to

retu

rn fo

r scr

eeni

ng in

3 ye

ars;

wom

en w

ho s

cree

ned

posi

tive

on a

ny o

f car

eHPV

, VIA

or c

ytol

ogy

wer

e re

ferr

ed to

col

posc

opy

and

dire

cted

bio

psy

Jero

nim

o et

 al23

Indi

a—U

ttar

Pra

desh

5Cl

inic

ian-

colle

cted

cer

vica

l +

self-

colle

cted

vag

inal

sw

ab46

58W

omen

invi

ted

for c

ervi

cal c

ance

r scr

eeni

ng b

y HC

W th

roug

h a

door

-to-

door

sur

vey

38 (3

0–46

)2.

9%0.

7%0.

3%Sc

reen

pos

itive

for a

ny o

f: VI

A, c

ervi

cal c

ytol

ogy,

car

eHPV

Indi

a—Hy

dera

bad

6Cl

inic

ian-

colle

cted

cer

vica

l +

self-

colle

cted

vag

inal

sw

ab45

02W

omen

invi

ted

for c

ervi

cal c

ance

r scr

eeni

ng36

(30–

42)

6.3%

1.7%

1.1%

Nic

arag

ua7

Clin

icia

n-co

llect

ed c

ervi

cal +

se

lf-co

llect

ed v

agin

al s

wab

4645

Wom

en in

vite

d fo

r cer

vica

l can

cer s

cree

ning

38 (3

2–44

)12

.6%

2.0%

1.4%

Uga

nda

8Cl

inic

ian-

colle

cted

cer

vica

l +

self-

colle

cted

vag

inal

sw

ab31

46W

omen

invi

ted

for c

ervi

cal c

ance

r scr

eeni

ng37

(29–

45)

20.2

%2.

8%0.

8%

Zhao

 et a

l22Ch

ina

9Cl

inic

ian-

colle

cted

cer

vica

l +

self-

colle

cted

vag

inal

sw

ab74

21Pr

evio

usly

uns

cree

ned

wom

en fr

om th

ree

com

mun

es(Y

angc

heng

, Xin

mi a

nd To

nggu

) inv

ited

for s

cree

ning

25–6

0 ye

ars

14.4

%1.

9%1.

3%Sc

reen

pos

itive

for a

ny o

f: VI

A, O

ncoE

6, H

CII a

nd c

areH

PV

Gag

e et

 al21

Irun,

 Nig

eria

10

Cerv

ical

sw

ab (D

igen

e ce

rvic

al

brus

h)38

2W

omen

refe

rred

to c

olpo

scop

y ba

sed

on a

bnor

mal

VIA

/LBC

or

HPV

PCR

and

a ra

ndom

sel

ectio

n of

scr

een

nega

tive

cont

rols

18–8

5 ye

ars

25.1

%3.

9%N

RSc

reen

pos

itive

for a

ny o

f: VI

A, L

BC H

PV P

CR a

nd ra

ndom

sel

ectio

n of

scr

een

nega

tive

cont

rols

Qia

o et

 al20

Shan

xi, C

hina

11Cl

inic

ian-

colle

cted

cer

vica

l +

self-

colle

cted

vag

inal

sw

ab25

30W

omen

; non

-pre

gnan

t, no

his

tory

of C

IN, p

elvi

c ra

diat

ion

or

hyst

erec

tom

y43

(37–

49)

18.0

%2.

9%1.

0%Sc

reen

pos

itive

for a

ny o

f: LB

C, H

CII,

care

HPV

Onc

oE6

stud

ies

Chib

wes

ha e

t al25

Lusa

ka, Z

amst

ics

of th

e in

clud

ed

publ

icat

ions

are

su

mm

abia

12Cl

inic

ian-

colle

cted

cer

vica

l19

9W

LHIV

age

d ≥

18 ye

ars

invi

ted

for s

cree

ning

≥18

year

s47

%†

16.0

%10

.0%

Scre

en p

ositi

ve fo

r any

of:

VIA,

dig

ital c

ervi

cogr

aphy

, Xpe

rt H

PV a

nd O

ncoE

6

Zhao

 et a

l22Ch

ina

9Cl

inic

ian-

colle

cted

cer

vica

l +

self-

colle

cted

vag

inal

sw

ab74

21Pr

evio

usly

uns

cree

ned

wom

en fr

om th

ree

com

mun

es(Y

angc

heng

, Xin

mi a

nd To

nggu

) inv

ited

for s

cree

ning

25–6

0 ye

ars

1.8%

1.9%

1.3%

Scre

en p

ositi

ve fo

r any

of:

VIA,

Onc

oE6,

HCI

I and

car

eHPV

ASC

US,

aty

pica

l squ

amou

s ce

lls o

f und

eter

min

ed s

igni

fican

ce; C

IN, c

ervi

cal i

ntra

epith

elia

l neo

plas

ia; H

CII,

Hybr

id C

aptu

re II

; HCW

, hea

lthca

re w

orke

rs; H

PV, h

uman

pap

illom

aviru

s; HR

HPV

, hig

h-ris

k HP

V; L

BC, l

iqui

d-ba

sed

cyto

logy

; NR,

not

repo

rted

;  VI

A, v

isua

l ins

pect

ion

usin

g ac

etic

aci

d; V

ILI,

visu

al in

spec

tion

usin

g Lu

gol’s

iodi

ne;

WLH

IV, w

omen

livi

ng w

ith H

IV.

† HR

-HPV

mea

sure

d us

ing 

Gen

e Xp

ert t

est (

5.6%

 acc

ordi

ng to

Onc

oE6)

, *H

R-HP

V pr

eval

ence

pre

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OncoE6 for the detection of CIN2+ and CIN3+There were two studies that evaluated the performance of OncoE6 for the detection of CIN2+22 25 among 7621 women and CIN3+ among 7421 women,22 and among 200 WLHIV.25 Zhao et al22 reported a sensitivity and specificity of 42.4% and 99.1%, respectively, for the detection of CIN2+, and 53.5% and 98.9%, respectively, for the detection of CIN3+ among HIV-negative women in China. In Zambia, Chibwesha et al25 reported a sensitivity and specificity of 31.3% (95% CI 16 to 50) and 99.4% (95% CI 97 to 100), respectively, for CIN2+ detection among WLHIV.

methodological assessmentAccording to the QUADAS criteria (online supplementary table 1), the quality of the papers included was acceptable, but with some omissions in reporting on the training of test operators, mechanism for blinding of index and reference test and how indeterminate results were handled.

dISCuSSIonThis review found that the careHPV test had good sensitivity and specificity for the detection of CIN2+ (88.1% and 83.7%, respectively) and CIN3+ (90.3% and 85.3%, respectively) using clinician-collected swabs. While specificity remained high when

using self-collected vaginal swabs, the sensitivity for CIN2+ and CIN3+ was lower than when using clinician-collected swabs (73.6% and 75.2%, respectively).

The pooled performance estimates in this review suggest that while the careHPV test has similar specificity to that reported for the Hybrid Capture II (HCII) assay, the sensitivity is lower than what has been previously reported in other meta-analyses of HCII performance.28 This is consistent with a recent meta-anal-ysis29 that directly compared the performance of the two assays and reported a relative sensitivity for the careHPV test compared with the HCII assay of 0.86 (95% CI 0.79 to 0.94) and relative specificity of 1.01 (95% CI 0.99 to 1.03) for CIN2+.

Compared with the other screening modalities, visual inspec-tion and cervical cytology, the careHPV test had higher sensi-tivity but similar specificity for the detection of CIN2+. In a meta-analysis of 21 studies from sub-Saharan Africa and India among over 58 000 women,7 8 VIA showed moderate sensitivity for the detection of CIN2+ (pooled estimate: 79.2%–82.4%) and specificity (84.7%–87.4%). VILI performed even better with higher sensitivity (CIN2+: 91.2%–95.1%; CIN3+: 93.8%) and similar specificity (CIN2+: 84.5%–87.2%; CIN3+: 83.8%). However, sensitivity has been reported to be as low as 50% in other studies.9 The wide variation in its performance is attributed to the subjective nature of test interpretation. High

Figure 2 Meta-analysis of the careHPV test performance (sensitivity and specificity) for CIN2+ detection using clinician-collected cervical swabs among 12 populations. *studies among women living with hIV

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rates of positivity have resulted in over-referral to colposcopy services and overtreatment.30 Despite this, a single round of VIA screening has been associated with a 25%–35% reduction in cervical cancer incidence, cervical cancer mortality and the frequency of CIN2+ lesions, in studies in Thailand, Ghana and Zambia.31–33

The careHPV test also performed better than cervical cytology. In a meta-analysis of studies evaluating performance of screening in Africa and India,8 cytology, whether using positive test result cut-offs of atypical squamous cells of unde-termined significance and greater (≥ASCUS), low-grade squa-mous intraepithelial lesions (≥LSIL) or high-grade squamous intraepithelial lesions (≥HSIL), had poor sensitivity for the detection of CIN2+ (range: 42.6 for ≥HSIL to 57.0% for ≥ASCUS) and CIN3+ (range: 51.6%–63.0%) but high spec-ificity (range: 92.8%–99.3% and 92.3%–99.0% for CIN2+ and CIN3+, respectively).

hPV-dna testing among women living with hIVThe careHPV test was shown to have good sensitivity but lower specificity for the detection of CIN2+ among WLHIV in Burkina Faso, South Africa and Uganda in this review compared with the general population,24 27 similar to what was reported for HCII among WLHIV in South Africa.34 HPV testing may

detect many transient infections, which do not progress to CIN2+, meaning that its specificity for high-grade CIN can be low. A recent review of HPV-DNA-based tests for the detection of cervical lesions reported that for a 10% increase in HR-HPV prevalence, HR-HPV-DNA-based test specificity for CIN2+ detection decreased by 8.4% (95% CI 8.0% to 8.8%),35 which has important implications for HIV-positive populations who have a high prevalence of HR HPV. Segondy et al also reported an increase in specificity with increasing CD4+ cell count and among women on antiretroviral therapy (ART), corresponding with a decrease in HR-HPV prevalence with increasing CD4+ cell count and prolonged duration of ART use. Studies have shown that women are at decreased risk of CIN2+ if ART is initi-ated at higher CD4+ counts (>500 cells/mm3),36 and prolonged ART duration and high CD4+ cell count are associated with a reduction in HR-HPV prevalence and persistence.37 38

The biggest contribution of POC-HPV testing is the possi-bility of decentralising screening, increasing the number of women who enter the screening and management process more promptly and therefore may ultimately contribute to the decrease of incidence of high-grade cervical lesions. The slightly lower sensitivity and specificity for vaginal self-sam-pling compared with clinician-collected cervical samples in this review were similar to that in a large meta-analysis that

Figure 3 Meta-analysis of the careHPV test performance (sensitivity and specificity) for CIN2+ detection using self-collected vaginal swabs among eight populations. *studies among women living with hIV

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reported a relative sensitivity of 0.88 (95% CI 0.85 to 0.91) and specificity of 0.96 (95% CI 0.95 to 0.97) for CIN2+ using vaginal self-sampling compared with clinician-collected cervical samples.39 However, the possibility of self-sampling may allow for an increase in uptake of testing especially in settings where self-sampling might be preferred for cultural or logistical reasons. A number of studies have evaluated the acceptability and feasibility of the self-sampling using the careHPV test, and for some the concordance of results. A study of 431 women in rural Roi-et Province in Thailand40 reported that 91% found the self-swabbing acceptable, 71% preferred the self-swab to a clinician swab and 95% returned for same-day follow-up. In a study among 518 women in El Salvador,41 38.8% preferred self-collection and 31.9% preferred provider collection. In a study among 194 women in Ghana (50% of whom are WLHIV), 76.3% women found self-collection very easy/easy to obtain, 57.7% preferred self-collection to clini-cian collection and 61.9% felt self-collection would increase their likelihood to access cervical cancer screening; in that study, the concordance of the careHPV test results between self-collected and clinician-collected samples was 94.2%.42 Hence, despite the lower sensitivity of the careHPV test using vaginal self-swabs in this review, self-collection coupled with POC testing has the potential to increase coverage of screening

and impact on disease rates. Prospective studies are warranted to compare the effectiveness of vaginal self-sampling over clin-ic-based cervical sampling in terms of numbers of CIN identi-fied and managed.

The low sensitivity but high specificity of the OncoE6 test, which targets HPV16, HPV18 and HPV45, for CIN2+ detec-tion suggests it may be useful as a ‘screen-and-treat’ or triage test; however, further studies are warranted, especially in settings where HPV vaccination has been introduced.

limitationsA major drawback of the evaluation of HPV POC tests against a relatively rare disease outcome such as CIN2+ is that it is not a direct comparison of the detection of the infection that may cause disease several years later. Most HR-HPV infections are transient and will not all cause severe histological changes. There-fore, a measure of persistent infection at two time points, or a marker of transformative or integrative infection, might increase specificity. Furthermore, it is believed that some HR-HPV types, such as HPV16, HPV18 and HPV45, might have greater onco-genic potential.

There was significant heterogeneity across studies (I2, table 2), which may be attributed to the variation in HR-HPV

Figure 4 Meta-analysis of the careHPV test performance (sensitivity and specificity) for CIN3+ detection using clinician-collected cervical swabs among eight populations. *studies among women living with hIV

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prevalence across studies. WLHIV in Burkina Faso, South Africa and Uganda had the highest prevalence (46.5%, 43.8% and 44.9%, respectively), but excluding these studies did not lead to a reduction in heterogeneity. HR HPV was also high among HIV-negative women in Uganda (20.2%), Nigeria (25.1%) and China (18.0%). Another study in Rwanda43 reported that the careHPV test positivity was higher among 1289 WLHIV compared with 1675 HIV-negative women (31.8% vs 8.2%, respectively), but the study did not measure its performance for CIN2+ detection.

There was potential bias attributed to biopsy indication in the included studies. Most studies maximised the chances of obtaining histological results by basing biopsy decision on positivity of any of the screening tests, which included visual inspection, cervical cytology and HPV-DNA tests. Women negative by all tests were considered to be at extremely low risk of CIN2 since in particular HPV DNA and cytology have very high negative predictive values for CIN2 diagnosis.44 There is potentially greater risk of ascertainment bias in studies with lower prevalence of HR HPV (table 2), especially among the studies that used self-collected vaginal specimens which had lower sensitivity for CIN2+. Relative accuracy esti-mates of the careHPV test compared with other HPV assays would allow for a comparability measure of the different HPV assays, taking into account the heterogeneity across studies

and the effects of sampling devices, quality and histological endpoint determination. There were too few studies evalu-ating the performance of the OncoE6 test to conduct a formal pooling analysis.

New tests for HPV detection, such as the Xpert HPV, look promising in terms of performance for the detection of CIN2+ compared with HC2 or HPV genotyping,25 45 46 but were not considered to satisfy the ASSURED criteria for this review. Over time and with lower costs, such tests may qualify, especially if investment is made in the platform, as is the case for countries like South Africa, which has introduced Xpert for Mycobacterium tuberculosis diagnosis nationwide.

ConCluSIonThe careHPV test performs as well as other screening modal-ities, such as visual inspection and cervical cytology, and has the added advantage of allowing for self-sampling that can increase coverage and uptake of screening. HPV-DNA testing is, however, less specific among WLHIV and could result in more false-positive results and over-referral for colpos-copy in this population. The possibility for future HPV-POC tests to distinguish between certain HPV types, to deter-mine persistence or transformation/integration stages, might improve on their performance.

Figure 5 Meta-analysis of the careHPV test performance (sensitivity and specificity) for CIN3+ detection using self-collected vaginal swabs among six populations.

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handling editor Jackie A Cassell

Contributors HK, PM and RWP conceptualised the study and developed the research protocol. HK and PM identified articles for full-text review. HK extracted data from studies that matched inclusion criteria. HK and NPP did the statistical analyses. All contributed to the writing of the manuscript.

Funding The authors of this manuscript received funding support from the UK Medical Research Council (MRC) PHINDS scheme (PH01/14-39).

Competing interests None declared.

Provenance and peer review Commissioned; externally peer reviewed.

open access This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http:// creativecommons. org/ licenses/ by/ 4. 0/

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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.5% Key messages

► Simplified and rapid HPV-DNA assays designed for use in resource-limited settings have recently become available, including the careHPV test and OncoE6.

► The careHPV test had good sensitivity and specificity for the detection of CIN2+ and CIN3+, but sensitivity was lower using self-collected vaginal samples.

► The specificity for CIN2+ was lower in high HPV prevalence populations such as women living with HIV.

► The possibility for future HPV-POC tests to distinguish between certain HPV types, to determine persistence or transformation/integration stages, might improve on their performance.

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screeningpoint-of-care tests for human papillomavirusstudies evaluating the performance of A systematic review and meta-analysis of

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